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1.
Birth Defects Research ; 115(8):844, 2023.
Article in English | EMBASE | ID: covidwho-20243926

ABSTRACT

Background: Studies suggest perinatal infection with SARSCoV- 2 can induce adverse birth outcomes, but studies published to date have substantial limitations. Most have identified cases based upon their presentation for clinical care, and very few have examined pandemic-related stress which may also impact adverse birth outcomes. Objective(s): To evaluate the relationships between SARSCoV- 2 infection in pregnancy and pandemic-related stress with birth outcomes. Study Design: We conducted an observational study of 211 mother-newborn dyads in three urban cohorts participating in the Environmental Influences on Child Health Outcomes (ECHO) Program. Serology for SARS-CoV-2 was assessed in a convenience sample of prenatal maternal, cord serum or dried blood spots from births occurring between January 2020-September 2021. Specimens were assessed for IgG, IgM, and IgA antibodies to nucleocapsid, S1 spike, S2 spike, and receptor-binding domain. A Pandemic-related Traumatic Stress (PTS) scale was based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition Acute Stress Disorder criteria. Result(s): 36% were positive for at least one antibody type, chiefly IgG. Self-report of infection was not significantly correlated with combined serology. There were no differences in gestational age (GA), birth weight, preterm birth (PTB), or low birth weight (LBW) among seropositive mothers. However, IgM seropositive mothers had children with lower BW (434g, 95% CI: 116- 752), BW Z score-for-GA (0.73 SD, 95% CI 0.10-1.36) and were more likely to deliver preterm (OR 8.75, 95% CI 1.22-62.4). Associations with LBW sustained in sensitivity analyses limited to pre-vaccine samples, and PTS symptoms were not associated with birth outcomes. The addition of PTS did not substantially change associations with BW, although associations with PTB attenuated to near-significance. Conclusion(s): We identified decreased birth weight and increased prematurity in mothers IgM seropositive to SARS-CoV-2, independent of PTS. Though there are limits to interpretation, the data support efforts to prevent SARS-CoV-2 infections in pregnancy.

2.
Cytotherapy ; 25(6 Supplement):S232-S233, 2023.
Article in English | EMBASE | ID: covidwho-20237943

ABSTRACT

Background & Aim: Immunological characteristics of COVID-19 show pathological hyperinflammation associated with lymphopenia and dysfunctional T cell responses. These features provide a rationale for restoring functional T cell immunity in COVID-19 patients by adoptive transfer of SARS-CoV-2 specific T cells. Methods, Results & Conclusion(s): To generate SARS-CoV-2 specific T cells, we isolated peripheral blood mononuclear cells from 7 COVID-19 recovered and 13 unexposed donors. Consequently, we stimulated cells with SARS-CoV-2 peptide mixtures covering spike, membrane and nucleocapsid proteins. Then, we culture expanded cells with IL-2 for 21 days. We assessed immunophenotypes, cytokine profiles, antigen specificity of the final cell products. Our results show that SARSCoV- 2 specific T cells could be expanded in both COVID-19 recovered and unexposed groups. Immunophenotypes were similar in both groups showing CD4+ T cell dominance, but CD8+ and CD3+CD56+ T cells were also present. Antigen specificity was determined by ELISPOT, intracellular cytokine assay, and cytotoxicity assays. One out of 14 individuals who were previously unexposed to SARS-CoV-2 failed to show antigen specificity. Moreover, ex-vivo expanded SARS-CoV-2 specific T cells mainly consisted of central and effector memory subsets with reduced alloreactivity against HLA-unmatched cells suggesting the possibility for the development of third-party partial HLA-matching products. In conclusion, our findings show that SARSCoV- 2 specific T cell can be readily expanded from both COVID-19 and unexposed individuals and can therefore be manufactured as a biopharmaceutical product to treat severe COVID-19 patients.Copyright © 2023 International Society for Cell & Gene Therapy

3.
Clinical Immunology ; Conference: 2023 Clinical Immunology Society Annual Meeting: Immune Deficiency and Dysregulation North American Conference. St. Louis United States. 250(Supplement) (no pagination), 2023.
Article in English | EMBASE | ID: covidwho-20237070

ABSTRACT

We conducted a retrospective study in the adult primary immunodeficiency clinic at UAB examining COVID-19 infection and COVID-19 antibody response from vaccination, natural infection, and immunoglobulin replacement from February 2021 to November 2022. Our goal was to determine if nucleocapsid and spike antibodies could be found in our PID patients and if these antibodies could be derived from natural infection, vaccination, or antibody replacement exclusively or combinatory. We hypothesized that increasing antibodies would be detected in our population as the COVID period extended. Two hundred and forty-five subjects were tracked over 336 clinic visits during this period. Our PID population included subjects with CVID, XLA, thymoma, hypogammaglobulinemia, IgA deficiency, IgG subclass deficiency, specific antibody deficiency, Down syndrome, IgM deficiency, and patients with recurrent sinopulmonary infections. We had 196 females and 45 males in our study. In our patient population, 47% of our patient had known COVID-19 infection. Of those 47%, 21% of those infected patients had COVID-19 at least twice. Of those infected, three did not have COVID-19 spike antibodies and chose not to get vaccinated either. Two of those patients were not on IVIG and one was on Pangyza. Of those infected, 70% (n = 80) were on IgG infusions compared to those uninfected, 77% (n = 96) were on IgG infusions. Of interest, we had three XLA patients and all three had COVID-19 infection in the summer 2021. Two of them tested positive for nucleocapsid and spike antibodies in high titers and they were receiving Gammagard or Gamunex infusions, suggesting that these immunoglobulin preparations contain COVID-19 antibodies. We are still in the process of analyzing our data to see if diagnosis, IgG preparations, date of testing, B cell numbers, and drugs play a role in producing nucleocapsid antibodies and high spike antibody titers.Copyright © 2023 Elsevier Inc.

4.
Germs ; 12(4):507-518, 2022.
Article in English | EMBASE | ID: covidwho-20234801

ABSTRACT

Introduction In this study, we aimed to monitor anti-spike and anti-nucleocapsid antibodies positivity in healthcare workers (HCWs) vaccinated with two doses of inactivated CoronaVac (Sinovac, China) vaccine. Methods Overall, 242 volunteer HCWs were included. Of the participants, 193 were HCWs without history of prior documented COVID-19 (Group 1), while 49 had history of prior documented COVID-19 before vaccination (Group 2). The participants were followed up for SARS-CoV-2 antibodies positivity at four different blood sampling time points (immediately before the second vaccine dose and at the 1st, 3rd months and 141-150 days after the second dose). We investigated the serum IgG class antibodies against SARS-CoV-2 RBD region and IgG class antibodies against SARS-CoV-2 nucleocapsid antigen by chemiluminescent microparticle immunoassay (CMIA) method using commercial kits. Results We found positive serum anti-RBD IgG antibody in 76.4% of the participants (71% in Group 1;98% in Group 2) 28 days after the first dose. When the antibody levels of the groups were compared at the four blood sampling time points, Group 2 anti-RBD IgG levels were found to be significantly higher than those in Group 1 at all follow-up time points. Although anti-RBD IgG positivity persisted in 95.6% of all participants in the last blood sampling time point, a significant decrease was observed in antibody levels compared to the previous blood sampling time point. Anti-nucleocapsid IgG antibody was positive in 12 (6.2%) of participants in Group 1 and 32 (65.3%) in Group 2 at day 28 after the first dose. At the fourth blood sampling time point, anti-nucleocapsid antibodies were found to be positive in a total of 20 (9.7%) subjects, 10 (6.1%) in Group 1 and 10 (23.8%) in Group 2. Conclusions In this study, it was determined that serum antibody levels decreased in both groups after the third month after the second dose in HCWs vaccinated with CoronaVac vaccine.Copyright © GERMS 2022.

5.
Cytotherapy ; 25(6 Supplement):S258-S259, 2023.
Article in English | EMBASE | ID: covidwho-20232306

ABSTRACT

Background & Aim: The new UCOE models we have recently developed, tested on many cell groups (including mouse ES and human iPS cells) and human mAb recombinant production studies as well, shows a powerful resistance to DNA methylation- mediated silencing and provides a higher and stable transfection profile. By the urgent need of vaccine development for COVID-19 during the pandemic, in this study we aimed to produce a potential recombinant vaccine by using the new generation UCOEs models of our own design. Methods, Results & Conclusion(s): Existing new-generation UCOE models and standard plasmid vectors to be used as control group were provided. Then, the sequences related to the PCR method were amplified for sufficient stock generation and cloning experiments. Verification in the plasmid vector was carried out in gel electrophoresis. Transfection of 293T cells was performed with clone plasmids carrying antigen genes and plasmids carrying genetic information of lentivirus units for the production of lentiviral vectors. Afterwards, 293T cells produced lentiviral vectors carrying antigen genes. Harvesting of these vectors was carried out during 48th and 72nd hours. Afterwards, CHO cells were transduced with appropriate quantity of lentiviral vectors. Isolation and purification of targeted proteins from the relevant medium were performed by HPLC and Q-TOF methods. A part of the spike and nucleocapsid gene sequences of COVID-19 were firstly cloned into our UCOE models. These UCOEs plasmids were then transferred into 293T cells along with plasmids carrying the genes that will form the lentivirus vectors (LVs). After harvesting and calculation of LV vector titers, the cloned vectors were then transfected into the CHO cells which the targeted recombinant production of the antigen proteins will be carried out. Antigenic structures were then isolated from the culture medium of CHO cells in following days for confirmation. Using HPLC and qTOF mass spectrometer methods, these structures in the medium were confirmed to be the units of spike and nucleocapsid proteins of the COVID-19 virus. In order to produce large amount of the recombinant antigens, the culture was then carried out with bioreactors in liters. At the final stage, these recombinantly produced antigen proteins were tested on rats to measure their immunogenic responses, and the study recently been completed successfully as a potential recombinant vaccine against COVID-19.Copyright © 2023 International Society for Cell & Gene Therapy

6.
International Journal of Infectious Diseases ; 130(Supplement 2):S132, 2023.
Article in English | EMBASE | ID: covidwho-2325221

ABSTRACT

Intro: Children and Young people were the last group in England be offered COVID-19 vaccination (from September 2021), thus were the largest susceptible group when SARS-CoV-2 Omicron variants emerged. We monitored vaccine and naturally-derived antibodies in schools between November 2021 and March 2022. Method(s): We conducted three large surveys (November 2021, January and March 2022) in a nationally representative random sample of primary and secondary schools, stratified by regions. Oral fluid samples were tested for IgG antibodies against SARS-CoV-2 nucleocapsid (anti-NP) and spike (anti-S1) proteins using novel validated ELISAs;vaccines used in England elicit anti-S1 antibodies only. We calculated weighted prevalences for each survey, and used multilevel logistic regression to investigate associations with socio-demographic factors. Finding(s): Overall 11311 students contributed 22478 biological samples (respectively 4840, 7549 and 10089 in rounds 1, 2 and 3, with similar socio- demographic characteristics). In 4-11 year olds, not eligible for vaccination, anti- S1 and anti-NP antibody prevalences were 31.3% and 26.6%, 46.2% and 43.8%, and 53.4% and 58.7% respectively over the three rounds. The corresponding estimates in 12 to 18 year olds) were 70.7% and 34.6%, 85.6% and 45.9%, 89.0 and 53.9%. In November 2021 (before Omicron dominance), higher anti-S1 antibody positivity was associated with older age and Black ethnicity, and non- eligibility for free school meals in 4-11 year olds. In 12-18 years it was associated with non-eligibility for free school meals. In March 2022 when Omicron dominated, these associations remained, together with urban location in 4-11 years old. Conclusion(s): The steep increase in 4-11 year olds in both sets of antibodies reflected the emergence and spread of highly infectious Omicron variants whilst high and increasing anti-S1 prevalence in secondary students was consistent with greater vaccine uptake. Socioeconomically deprived 12-18 year olds had lower odds of anti-S1, suggesting lower vaccine uptake or access.Copyright © 2023

7.
Infectious Diseases: News, Opinions, Training ; 10(3):23-32, 2021.
Article in Russian | EMBASE | ID: covidwho-2327473

ABSTRACT

Patients with end-stage chronic kidney disease treated with hemodialysis are at risk of infection and severe course of the new coronavirus infection. This opinion was based on the data obtained as a result of PCR testing during the active phase of the disease with detailed clinical symptoms. However, this diagnostic method does not allow one to fully assess the prevalence of infection in the population. The aim - studying of the frequency of SARS-CoV-2 infection in patients receiving hemodialysis treatment and the spectrum of antiviral antibodies, depending on the nature of the course of COVID-19. Material and methods. 100 patients with chronic kidney disease (stage 5D) treated at the outpatient Dialysis Center (MCVTP) were included in the study by a simple random sample. The assessment of SARS-CoV-2 infection was carried out by analyzing the material of smears obtained from the naso-oropharynx by PCR and blood serum samples by ELISA. The study excluded 14 patients with dubious results for the determination of serological markers SARS-CoV-2 and 1 patient with active infection, who was isolated from the RNA of the virus. Results. IgM and IgG antibodies were detected in 49 (57.6%) of the 85 examined patients. 24 of them (group 1) were diagnosed with COVID-19 infection with typical clinical symptoms 3-9 months ago, and 25 (group 2) had no clinical manifestations of the acute respiratory infection at the appropriate time suggesting an asymptomatic course of the disease. IgM class antibodies were detected with equal frequency in group 1 and in group 2 (33.3 vs 24.0%, respectively, p<0.6). IgG antibodies exclusively to the nucleocapsid N-protein (IgGn) were detected only in the latent form of the disease (32%), while antibodies against the S-protein (spike protein) of the virus (IgGs and IgGn+s) were detected more often in the manifest form compared to the asymptomatic one (100 vs 60%, respectively, p<0.05). Conclusion. In a random cohort of patient receiving hemodialysis treatment, more than half were asymptomatic.Despite a wide range of prevention measures, SARS-CoV-2 infection among patients treated with hemodialysis is more than 2 times higher than in the general population.Copyright © 2021 Geotar Media Publishing Group. All rights reserved.

8.
International Journal of Infectious Diseases ; 130(Supplement 2):S25, 2023.
Article in English | EMBASE | ID: covidwho-2327123

ABSTRACT

Intro: VLA2001 is a highly-purified, inactivated whole-virus SARS-CoV-2 vaccine based on a dual-adjuvant system of Alum and CpG1018 for induction of a robust immune response. The vaccine was designed using a well-established technology platform and has received full marketing authorization in Europe. In a pivotal Phase 3 trial, VLA2001 demonstrated superior neutralizing antibody geometric mean titers (GMT) to the comparator, AstraZeneca's AZD1222, as well as non-inferior seroconversion rates two weeks after priming. The extension of the Phase 3 trial evaluated safety and immunogenicity of homologous and heterologous booster vaccinations of VLA2001. Method(s): This is a randomized observer-blind controlled, pivotal trial conducted in the UK in participants aged >=18 years who were randomly assigned 2:1 to receive two doses of VLA2001 or AZD1222, 28 days apart. A booster with VLA2001 was administered to eligible participants at 7 to 8 months after priming. The primary safety outcome was the frequency and severity of any adverse event following the booster vaccination. The primary immunogenicity outcomes were the GMT and fold increase of neutralizing antibodies against SARS-CoV-2 two weeks after the booster vaccination. The study is registered under NCT04864561. Finding(s): A booster dose of VLA2001 is well-tolerated in both AZD1222 and VLA2001 primed participants. High neutralizing antibody titers and fold- increases were generated two weeks following a booster of VLA2001. Cross- neutralizing serological responses against Delta and the Omicron BA.4/BA.5 variants of concern are elicited following a homologous or heterologous booster dose in VLA2001 or AZD1222 primed participants, respectively. Additionally, VLA2001 induced broad T-cell responses with antigen-specific IFN-gamma producing T-cells against the Spike, the Nucleocapsid and the Membrane protein. Conclusion(s): Homologous and heterologous booster doses of VLA2001 demonstrated a favorable tolerability profile irrespective of priming and induced broadly reactive neutralizing antibodies against the ancestral virus and variants of concern, including the currently circulating BA.4/BA.5.Copyright © 2023

9.
Rheumatology (United Kingdom) ; 62(Supplement 2):ii48, 2023.
Article in English | EMBASE | ID: covidwho-2326724

ABSTRACT

Background/Aims The immune response to SARS-CoV-2 is known to be reduced in the immunocompromised. However, extent to which immunity is affected by immunosuppression in specific disease cohorts remains poorly characterised. Furthermore, implications of the ongoing vaccination booster programme require further study. Individuals with lupus nephritis (LN) require prolonged high-dose immunosuppression in order to maintain disease control, rendering them important to study in this context. We evaluated SARS-CoV-2 nucleocapsid and spike antibody response in this cohort during the Spring/Summer 2022 booster vaccine campaign. Nucleocapsid antibody indicates previous infection whilst spike antibody indicates previous infection and/or vaccination response. Titre of spike antibody to prevent infection is not known, but presence of antibodies is likely to protect against severe disease. Methods SARS-CoV-2 spike and nucleocapsid antibody were measured in adult patients with LN attending a tertiary centre rheumatology clinic. Data was collected retrospectively on disease, immunosuppression, vaccine status and history of natural exposure. Results 35 cases of LN were investigated, of which LN III, IV and V were predominant biopsy diagnoses. Regarding immunosuppressants, the Eurolupus Cyclophosphamide protocol had been used in the majority of patients to achieve initial control, with 3/35 patients still receiving pulsed courses at data collection. 18/35 were on Mycophenolate Mofetil;a further 13/35 had previously received this. 31/35 took at least 5mg Prednisolone daily;25/35 took Hydroxychloroquine;7/35 took Azathioprine;7/35 had previously been on Methotrexate, 3/35 took Tacrolimus;1/35 took Ciclosporin. Regarding B-cell depleting monoclonal antibody therapy, 13/35 had received Rituximab and 8/35 were receiving Belimumab. Antibody levels were measured between 4 weeks and 13 months after last dose of vaccination;mean duration was 6 months. 11/35 had confirmed COVID-19 infection;a further 8/35 reported a possible history. Of the 35, 32 (91%) had mounted detectable SARS-CoV-2 spike antibody above the bottom 10% of assay detection, indicating some immunity to vaccination or natural exposure. 20 (57%) had detectable nucleocapsid antibody, suggesting natural infection with antibody response. Only 2 (6%) had not mounted any antibody response. Of note, neither were fully vaccinated: one had 1 vaccination with blood test 8 months subsequent;one had 2 vaccinations with blood test 7 months subsequent. The latter was also notably on haemodialysis. All who received 3+ vaccinations had detectable spike antibody responses, as well as 75% of those who had received 2 vaccinations. Conclusion Our study is the first analysis, to our knowledge, of SARS-CoV-2 antibody response in a LN cohort. Whilst neutralising capacity and level of antibody providing protection remains under research, these findings provide at least some reassurance that individuals with LN on immunosuppression are capable of mounting an immune response against SARS-CoV-2. Further work is required to establish extent and duration of protection with serial vaccinations in this cohort.

10.
Topics in Antiviral Medicine ; 31(2):44, 2023.
Article in English | EMBASE | ID: covidwho-2313173

ABSTRACT

Background: Five variants of concern (VOCs) have dominated COVID-19 disease etiology since 2020-Alpha, Beta, Gamma, Delta, and Omicron-possessing over 150 defining genomic alterations. Here, we used global proteomic and genomic approaches to study the host responses and selective forces driving VOC evolution. Method(s): We infected Calu-3 human lung epithelial cells with 5 VOCs and 2 wave 1 (W1) controls and performed mass spectrometry abundance proteomics, phosphoproteomics, and mRNA sequencing at 10 and 24 hours post infection. We additionally performed affinity purification mass spectrometry (APMS) by individually expressing all VOC mutant viral proteins (52) and corresponding W1 forms in human cells to quantify differential virus-host protein-protein interactions. Data was integrated using network modeling and bioinformatics to pinpoint VOC-specific differences. Four novel mutant viruses were developed using reverse genetics technology to validate the impact of specific genomic alterations. Result(s): We discovered VOCs evolved convergent molecular strategies to remodel the host response by modulating viral RNA and protein levels (most notably of N, Orf9b, and Orf6), altering nucleocapsid phosphorylation, and rewiring virus-host protein complexes. Integrative systems analyses revealed that Alpha, Beta, Gamma, and Delta ultimately converged in the suppression of interferon stimulated genes (ISGs) relative to W1 viruses, but Omicron BA.1 did not, and Delta induced more pro-inflammatory genes compared to other VOCs. Altered regulation of ISGs correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b;for example, Omicron BA.1 depicted a 2-fold decrease in Orf6 expression. We identified mutations that alter expression of Orf9b (N D3L and N -3A del) and the novel VOC protein N* (N R203K/G204R), and confirmed Orf6 innate immune antagonism using recombinant virus technology. Remarkably, Omicron BA.4 and BA.5 regained strengthened innate immune antagonism compared to BA.1, which again correlated with enhanced Orf6 expression, though dampened in BA.4 by a mutation (D61L) that we discovered disrupts the Orf6-nuclear pore interaction. Conclusion(s): Collectively, our findings suggest SARS-CoV-2 convergent evolution overcomes human innate immune barriers, laying the groundwork to understand future coronavirus evolution associated with immune escape and enhanced human-to-human transmission.

11.
Topics in Antiviral Medicine ; 31(2):74, 2023.
Article in English | EMBASE | ID: covidwho-2313168

ABSTRACT

Background: T cells play a critical role in the adaptive immune response to SARS-CoV-2 in both infection and vaccination. Identifying T cell epitopes and understanding how T cells recognize these epitopes can help inform future vaccine design and provide insight into T cell recognition of newly emerging variants. Here, we identified SARS-CoV-2 specific T cell epitopes, analyzed epitope-specific T cell repertoires, and characterized the potency and cross-reactivity of T cell clones across different common human coronaviruses (HCoVs). Method(s): SARS-CoV-2-specific T cell epitopes were determined by IFNgamma ELISpot using PBMC from convalescent individuals with mild/moderate disease (n=25 for Spike (S), Nucleocapsid (N) and Membrane (M)), and in vaccinated individuals (n=27 for S). Epitope-specific T cells were isolated based on activation markers following a 6-hour peptide stimulation, and scRNAseq was performed for TCR repertoire analysis. T cell lines were generated by expressing recombinant TCRs in Jurkat cells and activation was measured by CD69 upregulation. Result(s): We identified multiple immunodominant T cell epitopes across S, N and M proteins in convalescent individuals. In vaccinated individuals, we detected many of the same dominant S-specific epitopes at similar frequencies as compared to convalescent individuals. T cell responses to peptide S205 (amino acids 817-831) were observed in 56% and 59% of individuals following infection and vaccination, respectively, while 20% and 19% of individuals responded to S302 (a.a. 1205-1219) following infection and vaccination, respectively. For S205, a CD4+ T cell response, we confirmed 8 unique TCRs and determined the minimal epitope to be a 9mer (IEDLLFNKV). While TCR genes TRAV8-6*01 and TRBV30*01 were commonly utilized across the TCRs, we did identify TCRs with unique immunogenetic properties with different potencies of cross-reactivity to other HCoVs. For S302, a CD8+ T cell response, we identified two unique TCRs with different immunogenetic properties that recognized the same 9mer (YIKWPWYIW) and cross-reacted with different HCoV peptides (Figure 1). Conclusion(s): These data identify immunodominant T cell epitopes following SARS-CoV-2 infection and vaccination and provide a detailed analysis of epitope-specific TCR repertoires. The prospect of developing a vaccine that broadly protects against multiple human coronaviruses is bolstered by the identification of conserved immunodominant SARS-CoV-2 T cell epitopes that cross react with multiple other HCoVs.

12.
Topics in Antiviral Medicine ; 31(2):139, 2023.
Article in English | EMBASE | ID: covidwho-2312936

ABSTRACT

Background: Current COVID-19 vaccines provide substantial protection against severe COVID-19, but they do not completely eliminate subsequent SARS-CoV-2 infections. We examined incidence of and immune differences against related but different common cold coronaviruses (ccCoV) as a proxy for response against a future emerging CoV among those with SARS-CoV-2 infection, COVID-19 vaccination, or neither exposure. Method(s): We assessed incidence of ccCoV (229E, HKU1, NL63, OC43) and rhinovirus/enterovirus infections among those with documented prior SARSCoV- 2 infection (n=493), prior COVID-19 vaccine, but no SARS-CoV-2 infection (n=1,568), or no prior SARS-CoV-2 infection or vaccination (n=2,874). We conducted a retrospective review of all individuals at Boston Medical Center that underwent a comprehensive respiratory panel polymerase chain reaction (CRP-PCR) test from November 30, 2020 to October 8, 2021 to estimate infection incidence. A subset within each group was assessed for coronavirus specific humoral and cellular immune responses, via pseudovirus neutralization and peptide stimulation T cell assays. Comparisons among the three groups were done using Chi-square and multi-variate Cox-proportional hazards models. Result(s): Incidence of symptomatic ccCoV was lower in those individuals with documented prior SARS-CoV-2 infection (1.0%) compared to those with COVID-19 vaccination (2.9%) or no prior SARS-CoV-2 exposure (1.8%, p = 0.01). Rhinovirus/enterovirus incidence was similar in all three groups (range 6.2 - 8.7%). Individuals with prior SARS-CoV-2 infection and those with previous COVID-19 vaccination had similar plasma neutralization against SARS-CoV-2, OC43, and 229E spike bearing pseudoviruses. SARS-CoV-2 (p = 0.01) and OC43 nucleocapsid (p = 0.02), but not spike specific peptides, yielded higher T cell responses in individuals with a prior SARS-CoV-2 infection as compared to those with COVID-19 vaccination or no prior SARS-CoV-2 exposure. Conclusion(s): Prior SARS-CoV-2 infection, but not COVID-19 vaccination, protects against subsequent related but different ccCoV symptomatic infection. This protection against symptomatic ccCoVs may be mediated by cellular responses to non-spike proteins. Future pan-coronavirus vaccines could be improved by including both spike and non-spike antigens.

13.
Topics in Antiviral Medicine ; 31(2):384, 2023.
Article in English | EMBASE | ID: covidwho-2312829

ABSTRACT

Background: Sero-studies of SARS-CoV-2 have used antibody (Ab) responses to spike (S) and nucleocapsid (N) antigens to differentiate mRNA vaccinated (S+/N-) from infected (S+/N+) individuals. We performed testing on wellcharacterized subjects to determine how repeated vaccination or infection, and time from those exposures, influence these Ab levels. Method(s): Samples from individuals with known infection status: prepandemic negative controls n=462;first-time infected n=237 (~45 days post);vaccinated after infection n= 34 (~40 days post-vaccination and ~180 days post-infection);fully vaccinated n=158 (~50 days post);boosted n=31 (~30 days post);breakthrough n=18 (~14 days post-infection);reinfected n=10 (varied). Longitudinal samples (n=51) from subjects with evidence of reinfection (symptoms and/or positive rapid antigen test), were tested to determine the impact of the order of infection and/or vaccination on the magnitude of the anti-S and anti-N IgG Ab detected in the blood. Testing was performed with MesoScale Diagnostics (Gaithersburg, MD) assay. Outcomes are presented in WHO International Binding Antibody Units (BAU/mL). The cutoff for a positive result was 18 BAU for S and 12 BAU for N. Result(s): The median amount of Ab (IQR) in BAU for each group (Figure A) was: pre-pandemic negative controls S 0.53(0.27,1.03), N 0.55(0.18,1.67);first-time infected S 114(51,328), N 70(29,229);vaccinated after infection S 4367(2479,4837), N 15(7,35);fully vaccinated S 998(586,1529), N 0.31(0.16,0.68);boosted S 2988(1768,3522), N 0.59(0.32,1.03);breakthrough S 2429(2032,3413), N 2.5(0.93,8.6);reinfected S 1533(486,4643), N 7.8(2.6,62). For the breakthrough and second infections 17% and 40% were seropositive to N, respectively. Longitudinal analysis (Figure B) of those with multiple infections showed that all those with a positive rapid antigen test for their second infection had an increase in N Ab. Conclusion(s): The prevalence of antibodies to nucleocapsid cannot be used to determine the proportion of individuals infected to SARS-CoV-2 in a vaccinated population. Booster, repeated, and breakthrough infections are associated with IgG Ab levels to S >400 BAU/mL. A majority of breakthrough infections did not elicit an Ab response to N. For those with repeated infection, a minority elicited antibody responses to N. This could be related to misdiagnosis or the burden of infection, as only those who were positive by rapid antigen assay (indicative of a high viral load) had an increase in N Ab.

14.
Topics in Antiviral Medicine ; 31(2):366-367, 2023.
Article in English | EMBASE | ID: covidwho-2312691

ABSTRACT

Background: COVID-19 in Africa was less severe with fewer reported cases, hospitalizations and deaths compared to other continents. However, the lack of adequate surveillance systems in Africa makes estimating the burden of infection challenging. Serosurveillance can aid in determining the frequency of infection within this population. This study is aimed to estimate SARS-CoV-2 seroprevalence, describe the SARS-CoV-2 antibody (Ab) levels, and examine associations of seroreactivity among Ugandan blood donors. Method(s): Samples were obtained from the Mirasol Evaluation of Reduction in Infections Trial (MERIT), a randomized, double blind, controlled clinical trial evaluating transfusion transmitted infections. MERIT blood donor samples (n=3,517) were collected from Kampala, Uganda between October 2019 to April 2022. Additional blood donor samples (n=1,876) were collected from around the country between November-December 2021. Samples were tested for Ab to SARS-CoV-2 nucleocapsid (N) and spike (S) using an electrochemiluminescence immunoassay assay (Meso Scale Diagnostics, Gaithersburg, MD) per manufacturer's protocol. Samples seroreactive to both N and S Ab were considered Ab positive to SARS-CoV-2. Seroprevalence among MERIT donors were estimated within each quarter. Factors associated with seroreactivity from November-December 2021 were assessed by chi-square test. Result(s): SARS-CoV-2 seroprevalence increased from < 2.0% in October 2019- June 2020 to 82.5% in January-April 2022. Three distinct peaks in seroreactivity were seen in October-November 2020, July-August 2021, and January-April 2022 (see Figure). Among seroreactive donors, median N Ab levels increased 9-fold and median S Ab 19-fold over the study period. In November-December 2021, SARS-CoV-2 seroprevalence was higher among donors from Kampala (58.8%) compared to more rural regions of Hoima (47.7%), Jinja (47.9%), and Masaka (54.4%;p=0.007);S seroprevalence was lower among HIV+ donors (58.8% vs. 84.9%;p=0.009). Conclusion(s): Blood donors in Uganda showed high prevalence of Ab to SARSCoV- 2 by March of 2022, indicating that the infection levels were similar to many other regions of the globe. Higher seroprevalence was observed in the capital compared to more rural areas in Uganda. Further, increasingly high antibody levels among seropositive donors may indicate repeat infections. The lower COVID-19 morbidity and mortality was not due to a lack of exposure of the virus, but other factors yet to be determined.

15.
Topics in Antiviral Medicine ; 31(2):216, 2023.
Article in English | EMBASE | ID: covidwho-2319925

ABSTRACT

Background: The unprecedented scale of the COVID-19 pandemic and rapid evolution of SARS-CoV-2 variants underscores the need for broadly active inhibitors with a high barrier to resistance. The coronavirus main protease (Mpro) is an essential viral enzyme required for viral polyprotein processing and is highly conserved across human coronaviruses. Pomotrelvir (PBI-0451) is a novel Mpro inhibitor currently completing phase 2 clinical trial. Here we describe the mechanism of action, broad activity against SARS-CoV-2 clinical isolates, combination studies with other SARS-CoV-2 inhibitors and favorable resistance profile of pomotrelvir. Method(s): The kinetic parameters of pomotrelvir Mpro inhibition and its interaction with nirmaltrevir were determined in a kinetic protease assay. The IC50s of pomotrelvir on mutant Mpro proteins were measured in an endpoint Mpro assay. Combination studies of pomotrelvir with remdesivir and molnupiravir were carried out in A549-hACE2 cells infected with SARS-CoV-2 NLuc virus. Activity against SARS-CoV-2 clinical variants was assessed by infection of A549-ACE2-TMPRSS2 cells followed by immunostaining of the viral nucleocapsid protein. Result(s): Pomotrelvir is a potent competitive inhibitor of SARS-CoV-2 Mpro (Ki =2.7 nM). Binding of pomotrelvir and the Mpro inhibitor nirmatrelvir to the active site is mutually exclusive. In the SARS-CoV-2 NLuc assay, pomotrelvir is additive when combined with remdesivir or molnupiravir, two nucleoside analogs targeting viral RNA synthesis. When the effect of Mpro substitutions previously selected in a resistance study of pomotrelvir were analyzed in an enzyme assay, only Mpro-N133H showed a significant increase in IC50 (45-fold). The catalytic efficiency of Mpro-N133H is reduced by 10-fold and the recombinant virus SARSCoV-2 (WA1) -N133H is not viable, suggesting that N133H has lower replicative fitness. Lastly, pomotrelvir exhibits broad activity against all SARS-CoV-2 clinical isolates tested to date, including five omicron variants. Conclusion(s): PBI-0451 is a potent competitive inhibitor of SARS-CoV-2 Mpro and is broadly active against SARS-CoV-2 clinical isolates including omicron variants. Results from inhibitor interaction studies support the potential combination of pomotrelvir with remdesivir and molnupiravir but not nirmatrelvir. Enzymatic characterization of in vitro selected pomotrelvir resistant variants indicates they either confer no resistance or have reduced fitness.

16.
Journal of Biological Chemistry ; 299(3 Supplement):S449, 2023.
Article in English | EMBASE | ID: covidwho-2319531

ABSTRACT

Lipid enveloped viruses replicate and bud from the host cell where they acquire their lipid coat. Lipid-enveloped viruses include dangerous pathogens such as coronaviruses (SARSCoV-2, etc.), filoviruses (Ebola virus and Marburg virus) and paramyxoviruses (Nipah virus, Hendra virus, etc.). Despite understanding some of the basics of how these viruses cause disease and enter host cells, not much is known on how these dangerous pathogens interact with host cell lipids to achieve new virion formation. The viral matrix or membrane protein regulates assembly and budding from the host cell membrane, connecting the viral lipid envelope to the viral nucleocapsid. Depending on the virus family, this assembly and budding may occur at the plasma membrane or the ER-Golgi intermediate compartment. This presentation will detail the biophysical and biochemical basis of how these emerging pathogens hijack host lipid membrane and metabolic networks to form new virus particles that undergo release from the host cell. These studies were funded in part by the National Institute of Allergy and Infectious Diseases (R01AI081077, AI158220, AI169896).Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

17.
Russian Journal of Infection and Immunity ; 13(1):75-90, 2023.
Article in English | EMBASE | ID: covidwho-2318262

ABSTRACT

Background. The COVID-19 pandemic has become a substantial global health crisis, unparalleled in world history. Infection dynamics can have specific characteristics in different countries due to social, economic, climatic, or geographic factors. Aim(s): to study features of SARS-CoV-2 collective immunity among the Armenian population. Materials and methods. A cross-sectional, randomized study of collective immunity was carried out according to a program developed by Rospotrebnadzor and the St. Petersburg Pasteur Institute, taking into account WHO recommendations. The study was approved by the ethics committees of the National Center for Infectious Diseases (Armenia) and the St. Petersburg Pasteur Institute (Russia). A volunteer cohort was formed (N = 6057), randomized by age and region. The study's analysis included: shares and distributions of antibodies (Abs) to nucleocapsid (Nc) antigen (Ag) and receptor binding domain (RBD) S-1 Ag in the cohort;and quantitative determination of these Abs by ELISA. During the survey, a history of vaccination was indicated by 4395 people. Results. Overall seropositivity formed in the whole cohort (by April 14, 2022) was 98.6% (95% CI: 98.1-98.7). It did not depend on age, place of residence, or occupation. When quantifying Nc and RBD Abs, the proportions of volunteers with Nc Ab levels of 1-17 BAU/ml and RBD Ab levels of 22.6-220 BAU/ml were the smallest, amounting to 6.9% (95% CI: 6.2-7.5) and 20.4% (95% CI: 19.4-21.4), respectively. With increasing serum concentrations (Nc > 667 BAU/ml, RBD > 450 BAU/ml), the proportions of individuals with the corresponding levels were 20.2% for Nc (95% CI: 19.2-21.3) and 54.2% for RBD (95% CI: 52.9-55.5). Vaccination coverage was 72.6% (95% CI: 71.5-73.7). The most frequently used were Sinopharm/BIBP (32.4%), AZD1222 (22.3%), and Gam-COVID-Vac (21%). The remaining vaccines (CoronaVac, mRNA-1273, BNT162b2, CoviVac) were used by 24.3% of vaccinated individuals. When summing vaccines by platform, it was found that: vector vaccines were used in 40.34% (95% CI: 33.57-42.39) of cases;whole-virion vaccines were used in 26.83% (95% CI: 24.76-32.20);and mRNA vaccines were used in 6.33% (95% CI: 4.84-8.91). Conclusion. The epidemic situation in Armenia by April 2022 was characterized by a high level of collective immunity, independent of age or regional factors. Vector and whole-virion vaccines have been used most widely.Copyright © Popova A.Yu. et al., 2023.

18.
Topics in Antiviral Medicine ; 31(2):113-114, 2023.
Article in English | EMBASE | ID: covidwho-2318101

ABSTRACT

Background: There is mounting evidence regarding the frequency and spectrum of post-acute sequelae of SARS-CoV-2 infection (PASC), but a search for causes has been elusive. Recently, a plasma-based assay for SARS-CoV-2 antigen has been developed, which in initial use revealed that a high fraction of severely affected patients with PASC had circulating antigen. It is unknown whether detectable SARS-CoV-2 antigen is specific for PASC or how the assay performs in a broader clinical spectrum of patients with PASC. Method(s): We evaluated a cohort of patients with RNA-confirmed SARS-CoV-2 infection enrolled >=3 weeks following initial symptoms. Participants, both with and without PASC at enrollment, were identified via facility- and communitybased advertising and examined every 4 months. An interviewer-administered questionnaire ascertained presence of 30 different symptoms (new or worse compared to pre-COVID) in the prior 2 days at each exam. Using the single molecule array (Simoa) assay, we measured spike, S1, and nucleocapsid SARSCoV- 2 antigens in plasma collected at time of symptom assessment. Result(s): We examined 172 participants (50% men, 46% non-white, median age 46 years) who contributed 667 timepoints from 0.7 to 15.4 months following infection, at which 66% featured report of >=1 symptom. Sixty-one of 667 timepoints (9.1%) representing 24% of persons had >=1 detectable SARSCoV- 2 antigen. Among the 437 timepoints at which >=1 symptom was present, 9.8% had >=1 detectable antigen;this compares to 7.8% of timepoints at which symptoms were absent. In comparison to those without symptoms, individuals with several specific symptom complexes (gastrointestinal, musculoskeletal, and central neurologic) more commonly had detectable antigen (Figure). Hospitalization during acute COVID-19 was strongly related to antigen detection. Conclusion(s): Among a diverse group of SARS-CoV-2-infected persons in the post-acute phase of infection, SARS-CoV-2 antigen is detectable in plasma in both those with and without symptoms but more commonly in those with gastrointestinal, musculoskeletal, and central neurologic complaints. The findings indicate that antigen persists in at least some persons and suggest (but do not prove) that antigen is causally related to symptoms. That antigen is found in only a fraction of those with PASC indicates either that not all symptoms are driven by antigen, current plasma antigen detection is insensitive relative to tissue, or nominal PASC symptoms are sometimes unrelated to SARS-CoV-2. (Figure Presented).

19.
Topics in Antiviral Medicine ; 31(2):368, 2023.
Article in English | EMBASE | ID: covidwho-2318038

ABSTRACT

Background: People who inject drugs (PWID) may be at a greater risk of SARS-CoV-2 infection and COVID-19 due to socio-structural inequities, high-risk behaviors and comorbidities;however, PWID have been underrepresented in case-based surveillance due to lower access to testing. We characterize temporal trends and correlates of SARS-CoV-2 seroprevalence among a community-based sample of current and former PWID. Method(s): A cross-sectional study was conducted among participants in the AIDS Linked to the IntraVenous Experience (ALIVE) study-a community-based cohort of adults with a history of injection drug use in Baltimore, Maryland. Participants' first serum sample collected at routine study visits between December 2020 and July 2022 was assayed for antibodies to the nucleocapsid (N) (past infection) and spike-1 (S) (past infection and/or vaccination) proteins using the MSD V-Plex Panel 2 IgG SARS-CoV-2 assay. For each correlate, we estimated adjusted prevalence ratios (PR) via separate Poisson regression models adjusted for calendar time, age, sex and race. Result(s): Of 561 participants, the median age was 59 years (range=28-77), 35% were female, 84% were Black, 36% were living with HIV (97% on ART), and 55% had received >=1 COVID-19 vaccine dose. Overall, anti-N and anti-S prevalence was 26% and 63%, respectively. Prevalence of anti-N increased from 23% to 40% between December 2020-May 2021 and December 2021-July 2022, with greater increases in the prevalence of anti-S from 34% to 86% over the same period (Figure). Being employed (PR=1.53 [95%CI=1.11-2.11]) and never being married (PR=1.40 [0.99-1.99]) were associated with a higher prevalence of anti-N, while female sex (PR=0.75 [0.55-1.02]) and a history of cancer (PR=0.40 [0.17-0.90]) were associated with a lower prevalence of anti-N. Younger age, female sex (PR=0.90 [0.80-1.02]), and homelessness (PR=0.78 [0.60-0.99]) were associated with a lower prevalence of anti-S. Although HIV infection was not associated with anti-N, it was associated with a higher prevalence of anti-S (PR=1.13 [1.02-1.27]). Substance use was not associated with anti-N or anti-S. Conclusion(s): Anti-N and anti-S levels increased over time, suggesting cumulative increases in SARS-CoV-2 incidence of infection and vaccination among PWID;however, disparities in seroprevalence remain. Younger and female PWID and those experiencing homelessness were less likely to be anti-S positive, suggesting programs should aim to improve vaccination coverage in such vulnerable populations.

20.
Topics in Antiviral Medicine ; 31(2):407-408, 2023.
Article in English | EMBASE | ID: covidwho-2316669

ABSTRACT

Background: Previous studies have demonstrated promising serologic responses in PLWH receiving a third dose of vaccine against SARS-CoV-2. However, real-world clinical effectiveness, especially during the pandemic caused by B.1.1.529 variant, remains less investigated. Method(s): PLWH seeking HIV care at our hospital from 2021/6 to 2022/6 were included and advised to receive the third dose of COVID-19 vaccine. Individuals were excluded from this study if they had been previously diagnosed with COVID-19. Different types of COVID-19 vaccines were available in the vaccination program, including BNT162b2, mRNA-1273 (either 50 or 100 mug), MVC-COV1901 and NVX-CoV2373 vaccines. PLWH were screening for the occurrence of COVID-19 through the reporting system of notifiable diseases of Taiwan CDC, and were tested for anti-nucleocapsid (anti-N) IgG every 1 to 3 months. Participants were followed for 180 days until the fourth dose of COVID-19 vaccination, occurrence of SARS-CoV-2 infection, seroconversion of anti-N IgG, death, or loss to follow-up, whichever occurred first. Result(s): 1,496 PLWH were included: 631 (42.2%) receiving 100 mug mRNA-1273 vaccine, 468 (31.3%) 50 mug mRNA-1273 vaccine, and 328 (21.9%) BNT162b2 vaccine, 65 (4.3%) MVC-COV1901 vaccine, and 4 (0.3%) NVX-CoV2373 vaccine for the third dose of SARS-CoV-2 vaccination. 297 (19.9%) PLWH were diagnosed with COVID-19 during the follow-up period, including 92 (14.6%) who received 100 mug mRNA-1273, 111 (23.7%) 50 mug mRNA-1273, 79 (24.1%) BNT162b2 and 15 (21.7%) either MVC-COV1901 or NVX-CoV2373;in addition, 98 PLWH had seroconversion of anti-N IgG during follow-up, including 23, 50, 19 and 6 PLWH who received 100 mug mRNA-1273, 50 mug mRNA-1273, BNT162b2, and either MVC-COV1901 or NVX-CoV2373, respectively. Similar rates of new infection with SARS-CoV-2 or seroconversion of anti-N IgG were demonstrated regardless the vaccine type of the third dose (log-rank test, p=0.46). Factors associated with a diagnosis of SARS-CoV-2 infection and seroconversion of anti-N IgG included an age >50 years (aOR, 0.67;95% CI, 0.49-0.91) and newly infected with hepatitis C virus (HCV) (aOR, 1.41;95% CI, 1.09-1.83). Conclusion(s): Our study demonstrated that clinical effectiveness of the third dose of different vaccines available to PLWH was similar in preventing SARSCoV- 2 infection or seroconversion of anti-N IgG Taiwan. PLWH aged less than 50 years and those with newly diagnosed HCV infection were at higher risk of acquiring COVID-19. Kaplan-Meier survival curve for acquiring COVID-19 or seroconversion of anti-N IgG in PLWH receiving different COVID-19 vaccination of the third dose (log-rank test, 4 groups, p = 0.46).

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